What is the treatment for retinal vasculitis associated with positive C-ANCA (Cytoplasmic Anti-Neutrophil Cytoplasmic Antibodies) and anti-PR3 (Proteinase 3), indicating Granulomatosis with Polyangiitis (GPA)?

Treatment of Retinal Vasculitis Associated with C-ANCA and Anti-PR3 (Granulomatosis with Polyangiitis)

For retinal vasculitis associated with C-ANCA and anti-PR3 positivity (Granulomatosis with Polyangiitis), the recommended first-line treatment is rituximab plus high-dose glucocorticoids for remission induction, followed by rituximab maintenance therapy. 1

Remission Induction Therapy

First-line therapy:

• Rituximab: 375 mg/m² once weekly for 4 weeks 1

  • Preferred over cyclophosphamide for extrarenal manifestations such as retinal vasculitis 1
  • Particularly effective in PR3-ANCA positive patients 2

• Plus high-dose glucocorticoids:

  • Initial dose: 1 mg/kg/day (not exceeding 80 mg/day) 1
  • With pre-specified tapering schedule 1
  • Usually preceded by IV methylprednisolone 1000 mg daily for 1-3 days in severe cases 3

Alternative therapy (if rituximab contraindicated):

• Cyclophosphamide: Either IV pulse (15 mg/kg every 2-3 weeks) or oral (2 mg/kg/day) 2
  • Plus high-dose glucocorticoids as above
  • Consider cumulative dose limitations (>36g associated with increased malignancy risk) 2

Maintenance Therapy

After achieving remission (typically within 3-6 months):

First-line maintenance:

• Rituximab: Two options 2, 1:
  1. 500 mg every 6 months for 18-24 months (MAINRITSAN protocol)
  2. 1000 mg at remission, then at months 4,8,12, and 16 (RITAZAREM protocol)

Alternative maintenance options:

• Azathioprine: 1.5-2 mg/kg/day for 18-24 months, then decrease to 1 mg/kg/day until 4 years after diagnosis 2
• Methotrexate: Consider if GFR >60 ml/min/1.73 m² 2
• Mycophenolate mofetil: Less effective than azathioprine but can be considered if other options not tolerated 2

Duration of Maintenance Therapy

• Minimum 18-24 months after achieving remission 2
• Consider longer treatment (up to 4 years) for patients with:
  • PR3-ANCA positivity (higher relapse risk) 2, 1
  • History of relapse 2
  • Persistent ANCA positivity 2

Monitoring and Follow-up

• Regular ophthalmologic examinations to assess retinal vasculitis response 1
• Monitor:
  • Complete blood count with differential
  • Renal function tests
  • Urinalysis
  • Inflammatory markers (ESR, CRP)
  • ANCA titers (though treatment decisions should not be based solely on ANCA results) 1

Management of Refractory Disease

If inadequate response to initial therapy:

1. Increase glucocorticoid dose (IV or oral)
2. Switch from cyclophosphamide to rituximab or vice versa
3. Consider plasma exchange in severe cases 2

Relapse Management

• For severe relapse: Rituximab is preferred over cyclophosphamide 1
• For non-severe relapse: Adjust current immunosuppressive therapy based on clinical features 1

Important Considerations and Pitfalls

Infection Prevention

• Pneumocystis jirovecii pneumonia prophylaxis is mandatory for patients receiving rituximab or cyclophosphamide 1
• Monitor for hypogammaglobulinemia, which occurs in up to 58% of patients treated with rituximab 3

Common Pitfalls to Avoid

1. Delaying treatment while waiting for additional testing in patients with compatible clinical presentation and positive ANCA serology 1
2. Premature discontinuation of maintenance therapy, which significantly increases relapse risk, especially in PR3-ANCA positive patients 1
3. Relying solely on ANCA titers to guide treatment decisions 1
4. Inadequate glucocorticoid tapering, which can lead to both relapse (if too rapid) or unnecessary toxicity (if too slow)

Special Considerations for Retinal Vasculitis

Retinal vasculitis in GPA can cause massive hemorrhages and significant visual impairment, but typically responds well to immunosuppressive therapy 4. Close ophthalmologic monitoring is essential to prevent permanent vision loss.

By following this treatment algorithm, patients with retinal vasculitis associated with C-ANCA and anti-PR3 positivity can achieve remission and prevent long-term ocular damage, significantly improving their morbidity, mortality, and quality of life outcomes.